Dr. Madalena Costa's career goal is to become an independent, academic investigator and faculty mentor. Her long-range goals are: (i) to understand basic mechanisms underlying nonlinear physiologic control in health and their degradation with aging and frailty, (ii) to develop a new class of dynamical biomarkers that quantify integrative physiologic function and give information about pathophysiology not obtainable with traditional probes, and (iii) to determine the value of the information encoded in the dynamical behavior of these biomarkers over time for risk stratification and the assessment of therapeutic interventions designed to reverse or retard pathologic aging. Her work is at the interdisciplinary interfaces of statistical physics, bioengineering, physiology, and the biology of aging. Two emerging themes of this interdisciplinary work are that healthy systems, which are marked by robustness and adaptability, exhibit the most complex multiscale dynamics, and that aging and the frailty syndrome in particular, are marked by a loss of complex multiscale variability and adaptive capacity. With the support of mentors, whose work spans diverse fields of biology, clinical medicine, physics, nonlinear dynamics and biostatistics that are essential facets of a broad-based training program, Dr. Costa proposes to pursue a career development plan that will enable her to further develop her expertise in complex systems in concert with state-of-the-art knowledge of the biology of aging and the clinical syndrome of frailty. Her basic research will address the following specific aims: 1) to elucidate nonlinear mechanisms of integrative physiologic control by developing dynamical biomarkers that quantify multiscale fluctuations;2) to test the hypothesis that the dynamical complexity of physiologic regulatory mechanisms degrades with aging in representative systems ranging from the cellular to organ, and 3) to test the hypothesis that loss of complexity in physiologic systems over time can be predictive of overall health status degradation and subsequent development of frailty. She will also use her experience to develop a training program in quantitative analysis of complex signals. RELEVANCE (See instructions): This work is of importance because it uses novel approaches and technologies to address a major public health problem, namely frailty in the elderly, which affects millions of Americans and others worldwide and is responsible for substantial morbidity and mortality and for billions of dollars of healthcare costs.